A one mg/dL elevation in baseline calcium levels was associated with a multivariable adjusted hazard ratio for mortality of 1.31 (95% CI 1.13 to 1.53, P<0.001), according to Csaba P. Kovesdy, MD, of the Salem, Va., Veterans Affairs Medical Center, and colleagues.

There also was a significant interaction between elevated baseline calcium level and the presence of cardiovascular disease, which raised the hazard ratio to 1.58 (95% CI 1.29 to 1.94, P<0.001), the researchers reported online in the Clinical Journal of the American Society of Nephrology.

Calcium and other mineral abnormalities are a recognized mortality risk in patients on dialysis, and authorities recommend maintenance of low-normal calcium levels for these patients.

In patients with non-dialysis-dependent kidney disease, however, the link had not been established, and the association with mortality had never been examined.

So Kovesdy and colleagues studied 1,243 patients with non-dialysis-dependent chronic kidney disease treated at their center between January 1990 and June 2007.

Patients' mean age was 68 years. Some 24% were black, and the mean estimated glomerular filtration rate was 37 mL/min per 1.73 m2.

To assess both short-and long-term consequences of abnormal serum calcium levels, the investigators analyzed the effects of calcium according to baseline and time-varying values. They also used time-averaged values.

Mean baseline and time-averaged corrected serum calcium levels were 9.4 mg/dL and 9.2 mg/dL, respectively, and patients had a median of 18 calcium measurements during follow-up.

By April 2009, some 698 patients had died, for a mortality rate of 123 per 1,000 patient-years (95% CI 114 to 132).

The association of mortality and time-averaged calcium was nonlinear, and compared with patients whose time-averaged calcium was 9.1 to 9.4 mg/dL (the referent level), patients with other levels had the following adjusted hazard ratios for mortality:

<9.1 mg/dL, 1.32 (95% CI 1.06 to 1.64)

9.41 to 9.7 mg/dL, 1.18 (95% CI 0.96 to 1.45)

>9.7 mg/dL, 1.42 (95% CI 1.13 to 1.78)

Time-varying calcium levels also had a nonlinear association with mortality, but only the lower levels had a trend toward higher mortality.

Compared with patients whose time-varying calcium level was 9.41 to 9.7 mg/dL, patients with other calcium levels had the following adjusted hazard ratios for mortality:

<9.1 mg/dL, 1.21 (95% CI 0.97 to 1.51)

9.1 to 9.4 mg/dL, 1.07 (95% CI 0.85 to 1.36)

>9.7 mg/dL, 1.06 (95% CI 0.85 to 1.33)

Moreover, the mortality risk associated with lower time-varying calcium was more pronounced in patients whose glomerular filtration rate exceeded 30 mL/min per 1.73 m2 and in those who did not receive calcium-containing phosphate binders.

The authors explained that in baseline and time-averaged analyses, which assessed long-term average exposure to calcium, higher levels of calcium were associated with increased mortality.

In contrast, in time-varying analyses that evaluated short-term outcome according to the last observed value, lower levels of calcium were associated with higher mortality.

These findings highlight the complexity of the pathophysiologic role of calcium, which stabilizes cell membranes and at low levels may increase neuromuscular excitability.

This "may explain why lower calcium levels in our time-varying models could have been associated with higher short-term death rates, possibly through a higher incidence of cardiac arrhythmias," they wrote.

In contrast, elevated calcium is thought to play a role in the development of cardiac calcification in patients with uremia.

"Such a mechanism of action could be a possible explanation for the increased mortality associated with higher time-averaged calcium levels in our study, because it appears more likely that prolonged exposure to higher serum calcium levels would be more likely to promote vascular calcification."

The study was limited by its historical and observational design, which can establish associations, but not causality.

It also was limited to men in a single institution, so the results may not be generalizable.

Furthermore, although the investigators hypothesized that the associations of low and high calcium with mortality derived from cardiovascular events, cause-specific mortality data were not available, so this could not be determined.

The researchers concluded that because both chronic hypercalcemia and acute hypocalcemia were associated with increased mortality in patients with non-dialysis-dependent chronic kidney disease, maintenance of normal levels may be beneficial for this population.

Prospective studies will be needed, however, to establish the target range for calcium and how best to achieve it.

Two of the investigators have received grant support and/or honoraria from Genzyme, Shire, and Fresenius.

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